Thiocarbamic acid derivatives

ABSTRACT

Compounds of the formula:   WHEREIN X is sulphur, oxygen, NR1, CO, CHR1 or CR1 wherein R1 is hydrogen or straight branched chain lower alkyl, Y is a straight or branched chain aliphatic moiety of one to three carbon atoms, or said aliphatic moiety linked to X by a double bond, R is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylmercapto or trifluoromethyl, N IS 1, 2 OR 3, AND Ar is an unsubstituted or substituted aromatic moiety, ARE PRODUCED BY REACTING A COMPOUND OF THE FORMULA:   WHEREIN X, Y, R and n are as above defined with a thiocarbonic acid ester halide of the formula:

United States Patent [191 Biishagen et al.

[ TI-IIOCARBAMIC ACID DERIVATIVES [75] Inventors: Horst Biishagen,Haan/Rhld;

Manfred Plempel, Wuppertal-Elberfeld, both of Germany [73] Assignee:Bayer Aktiengesellschait,

Leverkusen, Germany [22] Filed: Sept. 27, 1972 [211 App]. No.: 292,484

Related US. Application Data [62 Division of Sci. No. 25,557, April 3,1970. Pat. No.

[30] Foreign Application Priority Data Apr. 15, 1969 Germany 1917739[52] US. Cl 260/243 R; 424/246;260/304; 260/327 B; 260/244 R; 260/307D;-260/333; 260/239 BB, 260/287 R; 260/326.ll

[5 l] Int. Cl. C07d 93/12 [58] Field of Search 260/243 R I [56]References Cited UNITED STATES PATENTS Zivkovic et al. 260/243 PrimaryExaminer-John M. Ford Apr. 29, 1975 [57] ABSTRACT Compounds of theformula:

Y Ar-OCS-N wherein X, Y, R and n are as above defined with athiocarbonic acid ester'halide of the formula:

Hal CS 0 Ar wherein Hal is halogen and Ar is as above defined. Thesecompounds are useful as antimycotics for the treatment of fungalinfections which are pathogenic to humans and animals.

12 Claims, No Drawings THIOCARBAMIC ACID DERIVATIVES This is a divisionof application Ser. No. 25,557 filed Apr. 3, 1970 now U.S. Pat. No.3,729,473.

The present invention is concerned with thiocarbamic acid derivatives,toa process for their produc- 5 tion, to pharmaceutical compositionsuseful for the treatment of mycotic infections and to methods oftreating mycotic infections in humans and animals.

More particularly, the present invention is concerned with compounds ofthe formula:

Ar-OCS- (I) H wherein X, Y, R and n are as above defined, with athiocarbonic acid ester halide of the formula:

(Ill) wherein Hal is halogen and Ar is as above defined.

lt is preferred that the lower alkyl, lower alkoxy and loweralkylmercapto moieties set forth above contain from I to 4 carbon atomsin the alkyl portion. These moieties may be straight'or branched chain.

The preferred halogens are fluorine, chlorine or bromine.

The preferred aromatic moieties are those which contain up to 12 carbonatoms in the aromatic portion and the preferred moieties are phenyl andnaphthyl. 0 The preferred substituents on the aromatic moieties arehalogen, especially fluorine, chlorine or bromine, lower alkyl or loweralkoxy, and particularly lower alkyl of one to four carbon atoms orlower alkoxy of one to four carbon atoms.

Heterocyclic compound (ll) may be used in the form of a salt.

According to one embodiment of the process of the present invention thesodium salt of the heterocyclic base (ll) is first formed (e.g. in asuitable solvent such as hexamethylphosphoric acid triamide-(HMPA),dimethyl formamide (DMF) toluene or benzene) with the use of, forexample, sodium hydride, and is subsequently reacted with thethiocarbonic acid ester chloride at a slightly elevated temperature(about 30 to about 50 C).

Obviously, it is also possible to react the heterocyclic base as suchwith the carbonic acid ester chloride in a suitable solvent. for exampleCHCL CH Cl benzene, toluene, ethanol, methanol or acetone, and with theaddition of a tertiary base, for example triethylamine orN,N-dimethyl-benzylamine.

The heterocyclic bases and ester halides used as starting material areknown and can be obtained by known methods.

Working up of the reaction mixtures may be carried out in the usual way.

The excellent antimycotic effect of the newly prepared compounds issurprising and could not be foreseen, since after the elaborateinvestigations of T. Noguchi, Y. Hashimoto, K. Myazaki and A. Kayi, J.Pharm. Soc. Japan, 88 (2), 227-234 (1968), 88 (3), 335-343 (1968), 88(3)344-352 (1968) and 88 (3), 353-358 1968) it has hitherto been assumedthat only compounds of the type Ar -o-sCl l-Ar have an antimycoticeffect and even these only if R de- Table 1 Minimum inhibitionconcentration 'y/pcr ml test medium without serum with serumTrichophyton mentagroph. l y l -y Trichophyton equinum l -y 4 yTrichophyton verucosum l y l 'y Trichophyton rubrum var. Algochonosa l yl Trichophyton rubrum var. Ycsosa l y l y Trichophyton conccntricum l -yTrichophyton schoenlcin 4 y Microsporum fclincum l y Microsporumaudouinii l y Microsporum gallinac 40 -y l y 50% inhibition Chromomyccscarrioni 40 y l y 40 y l 7 507: inhibi- 50% inhibition tionEpidcrmophyton floccos. l -y 4 y Nocardia brasilicnsis 4 'y 50%inhibition Candida albicans y Sporotrichum 40 'y 40 'y C ryptococcusneoformans 40 -y 40 y Madurcllc grisca 40 'y 40 'y Histoplasmacapsulatum 4 7 l -y Allcschcria boydii 40 7 40 'y Phialophora pedrosoi40 'y 40 y Pcnicillium commune [00 y Aspergillus nigcr 100 7 HM) yANTIMYCOTIC EFFECT lN ANIMAL TEST The representative compound tested inTable 1 exhibits a very good effect in a model experiment withtrichophytia caused in guinea pigs by Trichophyton mentagrophytes, when0.5 and 1% solutions were locally applied once daily, starting with thethird day after infection, until the eighth day after infection. A rapidretrogression of the primary symptoms of infection (reddening of theskin and loss of hair) takes place, and the animals can be consideredcompletely cured on the 10th day after infection. A typical course ofinfection is illustrated in Table 2.

as well as Microsporon species, particularly Microsporlm canis andfelineum.

In general, it has proved advantageous to administer locallyformulations containing about 1% to about 2% Table 2 Test groupsEvaluation of course of infection after days post infection Untreated 12 3 4 5 6 7 8 9 10 control:

1st animal 0 0-1 0-1 1 2 2-3 3 4 4-5 5 2nd animal 0 0-1 0-1 1 l-2 2 33-4 4 4-5 3rd animal 0 0-1 0-1 1 1-2 2-3 3 4 5 5 Substance (a) (ofExample 1 171 1st animal 0 0-1 1 l l l l l l 2nd animal 0 0-1 1 l 0-10-1 0-1 0-1 0-1 0-1 3rd animal 0 0-1 1 1 1 l 1 1 1 Substance (b) 17: ascontrol 1st animal 0-1 l 1 0-1 1 1-2 2-. 2 2nd animal 0-1 1 1 1 l 1-2 22-1 Substance (c) 171 1st animal O-l l 1 O-1 1 1-2 l-2 l-2 2nd animal0-1 1 1 0-1 0-1 1 l-2 l-2 3rd animal 0-1 0-1 1 0-1 0-1 1 1 2 Substance(d) 171 animal O-l O-l 0-1 O-l l l l 1 2nd animal 0-1 0-1 0-1 0-1 O-l 00 (1 3rd animal 0-1 0-1 0-1 0-1 1 1 1-2 1- Substance (e) 1% 1st animal 11-2 0-1 0-1 O-l l l 1 2nd animal 1 1-2 1 0-1 0-1 1 l 1 3rd animal ()-11-2 0-1 0-1 0-1 0-1 0-1 0-1 4th animal 1 1 0-1 0-1 0' 0-1 0-1 0-1 Intable 2, substance (a) compound of Example 1 ocarbonyl]-aniline (forcomparison).

(c) compound of Example 24.

(d) compound of Example 25.

(e) compound of Example 42.

3-methyl-N-methyl-N-[ naphthyl-( 2 )-oxy-thiat which application takesplace. In some cases it may be sufficient to use less than the aforesaidminimum amount whereas in other cases it will be necessary to go beyondthe aforesaid upper limit. If larger amounts are administered, it may beadvisable to distribute these over the day in several individual doses.The same range of dosage is envisaged for application in humanExplanation of numbers: 1 reddening; 2 reddenmedicine, and the otherexplanations given above apply ing and beginning of loss of hair; 3strong loss of hair; 4 beginning of bleeding ulceration; 5 expansivebleeding ulcerations.

A primary fungicidal effect on Dermatophytes could be found in theWarburg test for the new compound (a) 5 at concentrations of 0.2 to 1A/ml substrate.

The compounds of the present invention are useful for the treatment offungal infections in both humans and animals. With regard to theveterinary medicine aspects, they have been found especially suitablefor analogously.

The compounds of the present invention can be applied alone or incombination with pharmaeeutieally acceptable diluents or carriers.Suitable forms for application in combination with various inertcarriers are powders, sprays, aqueous suspensions, elixirs, syrups andthe like. Such carriers comprise solid extenders or fillers, a sterileaqueous medium as well as nontoxic organic solvents and the like. 1n theaforesaid case. the therapeutically active compound should be present ata concentration of about 0.5 to per cent by weight of the totalmixtures, that is to say in quantities which suffice to achieve theabove range of dosage.

1n the case of aqueous suspensions and/or elixirs, the active ingredientcan be used together with diluents such as water, ethanol, propyleneglycol, glycerol and similar compounds or combinations of this type.

The invention further provides a medicament in dosage unit formcomprising at least one of the new active compounds either alone or inadmixture with a solid or liquid diluent or carrier. The medicament mayinclude a protective envelope containing the active compound and, ifused. the diluent or carrier.

The term medicament in dosage unit form as used in the presentspecification means a medicament as defined above in the form ofdiscrete portions each containing a unit dose, or a multiple orsub-multiple of a 1 unit dose of the active compound or compounds. Suchportions may, for example, be in monolithic coherent form. such astablets, suppositories, pills or dragees; in wrapped or concealed form,such as wrapped powders, cachets. sachets, or capsules; in ampoules.either free or as a sterile solution suitable for parenteral injection;or in any other form known to the art.

The invention also provides a method of combating fungus infections inhumans and animals (especially domestic animals) which comprisesapplying to the ani- 2 mals at least one of the new active compoundseither alone or in admixture with a solid or liquid diluent or carrier.

The following non-limitative example more particularly illustrates thepresent invention.

EXAMPLE 37.8 g (0.25 mol) 2,3-dihydro-l,4-benzothiazine were dissolvedin 250 ml hexamethyl-phosphoric acid triamide and 11.3 g (0.25 mol)sodium hydride (53.3% in paraffin) were added. The mixture was stirredat room temperature until the evolution of hydrogen had stopped (aboutminutes). Subsequently, 55.7 g (0.25 mol) O-B-napthyl-thiocarbonic acidester chloride were slowly added, the mixture was stirred at roomtemperature for 15 minutes and then at C for 15 minutes. The reactionsolution was poured into 2.5 litres of water, the precipitated crudeproduct was filtered off with suction, the adhering smears were removedby stirring with some acetone, and the product was recystallised formdioxan/ethanol.

64.5 g (76.5%)2,3-dihydro-N-[naphthyl-(2)-oxythiocarbonyH-l,4-benzothiazine wereobtained in the form of slightly yellowish prisms of m.p. 133 C.

The following compounds were obtained in an analogous way:

2.3-Dihydro-6-methyl-N-[ naphthyl-( 2 )-oxythiocarbonyll-l,4-benzothiazine. After recystallisation from dioxan/ethanol, thecompound forms colourless small cuboids of m.p. 128 C.

3. 2,3-Dihydro-6-trifluoromethyl-N-1naphthyl-(2)- oxy-thiocarbonyl l- 1.4-benzothiazine. Colourless coarse prisms from dioxan/ethanol; m.p. 126C.

2,3-Dihydro-2.6-dimethy1-N-[naphthyl-(2)-oxy- 62,3-Dihydro-2-methyl-N-[naphthyl-(2)-oxy- Colourless prisms of m.p. 164C from dioxan/e- 8. 2,3-Dihydro-N-[4-chlorophenoxy-thiocarbonyl]-1,4-benzothiazine. Shiny colourless scaly flakes (dioxan/ethanol) ofm.p. C.

' 9.2,3,4,5-Tetrahydro-N-[naphthyl-(2)-oxythiocarbonyl]-1,5-benzothiazepine.After recrystallisation from dioxan ethanol. colourless small prisms ofm.p. 167 C.

10. 2.3-Dihydro-N-[naphthyl-(Z)-oxy-thiocarbonyl]- l ,4-benzoxazine.Colourless broad prisms (dioxan) of m.p. 181 C. 1 1.2,3-Dihydro-6-methyl-N-[naphthyl-(2)-oxythiocarbonyl1- l ,4-benzoxazine.Colourless prisms of m.p. 143 C from dioxan. 12.2,3-Dihydro-6-methoxy-N-[naphthyl-( 2)-oxythiocarbonyl]-1,4-benzoxazine. Colourless prisms (dioxan/ethanol)of m.p. 158 C. 13.2,3-Dihydro-2,7-dimethyl-N-[naphthyl-(2)-oxythiocarbonyl]- 1,4-benzoxazine. Colourless small prisms (dioxan/ethanol) of m.p. 144 C.

14. 2,3-Dihydro-2-methyl-N-[naphthyl-(2)-oxythiocarbonyl]-l,4-benzoxazine. Colourless prisms of m.p. 158 C from dioxan/ethanol.

15. 2,3-Dihydro-2,6-dimethyl-N-[naphthy1-( 2 )-oxythiocarbonyl 1,4-benzoxazine. After recrystallisation from dioxan/ethanol. colourlessprisms of m.p. 132 C.

16. 2,3-Dihydro-2-methyl-6-methoxy-N-[naphthyl-(2)-oxy-thiocarbonyl]-1,4-benzoxazine. Colourless rectangular flakes(dioxan/ethanol) of m.p. 151 C.

17. 2.3-Dihydro-N-lnaphthyl-(2)-oxy-thiocarbonyl]- indole. Colourlessprisms of m.p. 162 C from dioxan/ethanol.

18. 2,3-Dihydro-2-methyl-N-[ naphthy1-( 2 )-oxythiocarbonyll-indole.Colourless prisms of m.p. 138 C from dioxan. 19.l,2,3,4-Tetrahydro-N-[naphthyl-(2)-oxy-thiocarbonyl]-quinoline. Almostcolourless prisms of m.p. 122 C from dioxan- /ethanol.

20. l,2,3,4-Tetrahydro-6-methyl-N-[naphthyl-(2)oxy-thiocarbonyll-quinoline. After recrystallisation from ethanol,colourless, thin, matted small needles of m.p. 128 C.

21. 1,2,3,4-Tetrahydro-2-methyl-N-[ naphthyl-( 2oxy-thiocarbonyll-quinoline. Colourless thin small needles of m.p. 147 Cfrom dioxan/ethanol.

22. 1,2.3,4-Tetrahydro-5-methyl-N-[naphthyl-(2)-oxy-thiocarbonyl]-quinoline. Colourless prisms (from ethanol) of m.p.121 C 23. l,2,3,4-Tetrahydro-7-methyl-N-[naphthyl-(2)-oxy-thiocarbonyl]-quinoline.

Colourless small needles (from ethanol) of m.p. 1 14 1 24.1.2,3,4-Tetrahydro-8-methyl-[naphthy1-(2)-oxythiocarbonyll-quinoline.After recrystallisation from ethanol, colourless flakes of m.p. 102 C.

25. 1,Z-Dihydro-4,6-dimethyl-[naphthy1-( 2)-oxy-thiocarbonyl1-quinoline. After recrystallisation fromdioxan/ethanol, the compound forms yellowish crystals of m.p. 124 C.

Table 3 Continued Com- Acid Reactant Base Reactant pound No.

l l B-Naphthyl-thiocarbonic 2,3-Dihydro-6-methylacid ester chloridel,4-benzoxazine Boiling p. 0.0 l/72 l2 B-Naphthyl-thiocarbonic2,3-Dihydro-6-methoxyacid ester chloride l,4-benzoxazine M.p. 59(platcs/ cyclohexane) l 3 B-Naphthyl-thiocarbonie 2,3-Dihydro-2,7-diacidester chloride methyl-lA-benzoxazine B.p. 0.l/7779 l4 B-Naphthyl-thiocarbonic 2,3-Dihydro-2-methylacid ester chlorideL4-benzoxazine B.p. 0.2/74 l5 B-Naphthyl-thiocarhonic 2.3-Dihydro-26-diacid ester chloride methyI-IA-benzoxazine B.p. 0.0l/74-76 l6fl-Naphthyl-thiocarbonic 2,3-Dihydro-2-methyl-6- acid ester chloridemcthoxyl 4-benzoxazine B.p. 0.5/134-l38" l 7 ,B-NaphthyI-thiocarbonic2,3-Dihydro-indole acid ester chloride l 8 B-Naphthyl-thiocarbonic 23-Dihydro-2methylacid ester chloride indole l9 fi-Naphthyl-thiocarbonicl .2,3,4-Tetrahydroacid ester chloride quinoline B-Naphthyl-thiocarhonicl ,2 3,4-Tetrahydro-6- acid ester chloride methyluinoline B.p. 0.7 97-982l B-Naphthyl-thiocarbonic l ,2,3,4-Tetrahydro-2- acid ester chloridemethyl-quinoline 22 B-Naphthyl-thiocarhonic L23 ,4-Tetrahydro-5- acidester chloride methyl-quinoline B.p. 0.l/69-70 23B-Naphthyl-thiocarhonic l 2.3.4-Tetrahydro-7- acid ester chloridemethyl-quinoline B.p. 3/ll4-ll6 24 B-Naphthyl-thiocarhonic l,2,3,4-Tetrahydro-8- acid ester chloride methyl-quinoline B. l2/l26-l27"25 [3-Naphthyl-thiocarhonic l ,S-Dihydro-k-dimethylacid ester chloridequinoline B.p. 0.5/98-l03 26 B-Naphthyl-thiocarbonicl,2-Dihydro-4-methylacid ester chloride quinoline B.p O.4/80 274-Fluorophenyl-thiol ,2.3,4-Tetrahydro-5- carbonic acid estermethyl-quinoline chloride 28 4-Chlorophenyl-thiol ,2,3,4-Tetrahydro-8-carbonic acid ester methyl-quinoline chloride 29 B-Naphthyl-thiocarbonicl,2,3,4-Tetrahydro-4- acid ester chloride oxo-quinoline 30B-Naphthyl-thiocarbonic l ,2.3,4-Tetrahydro- 1- acid ester chloridemethyl-6-methylmercaptoquinoxaline B.p. 0.5/164-166-l68" 3 iB-Naphthyl-thiocarbonic l ,2,4,5-Tetrahydro-2- acid ester chloridemcthyl-l-ethyll ,S-benzodiazepine M.p. 5 l 32 4-Chlorophenyl-thio-2,3-Dihydrol ,4-benzoxacarbonic acid ester zinc chloride 33B-NaphthyLthiocarhonic 2,3,4.5-Tetrahydro-2- acid ester chloride methyll.S-benzothiazepinc B.p. 0.0l/80-83 34 B-Naphthyl-thiocarbonic l,2.3.4-Tetrahydro-3- acid ester chloride methyl-quinoline B.p. 0.l5/7435 B-Naphthyl-thiocarbonic l.2.3.4-Tetrahydro-6.8-

acid ester chloride dimethyl-quinolinc B.p. 0.0l/70-72 36B-Naphthyl-thiocarbonic l 2.3 .4-Tetrahydro-4,6.7-

acid ester chloride trimethyl-quinoline B.p. ().4/l02-l05 M.p. 55(Prismen/Ligroin) 37 B-Naphthyl-thiocarbonic l .2,3,4-Tetrahydro-3 .8-

acid ester chloride dimethyl-quinoline B.p. 0.5/89-9() 384-Chlorophenyl-thio 1.2.3 .4-Tetrahydrocarbonic acid ester quinolinechloride 39 4-Chlorophenyl-thiol 2,3.4-Tetrahydro-6- carbonic acid estermethyl-quinolinc chloride 40 4-Chlorophenyl-thiol .2,3,4-Tetrahydro-2-carbonic acid ester chloride methyl-quinoline Table 3 Continued Com-Acid Reactant Base Reactant pound No.

41 4-Chlorophenyl-thiol,2,3,4-Tetrahydro-3- carbonic acid estermethyl-quinolinc chloride 42 4-Chlorophcnyl-thiol ,2,3,4-Tetrahydro-4-carbonic acid ester methyl-quinoline chloride 43 4-Chlorophenyl-thiol,23,4-Tctrahydro-4,6-

carbonic acid ester dimethyl-quinoline chloride 44B-Naphthyl-thiocarbonic I ,Z-Dihydro-quinoline acid ester chloride 45fi-Naphthyl-thiocarbonic acid ester chloride qulnohne B.p. 0.1/69-74 46B-Naphthyl-thiocarbonic l ,Z-Dihydro-B-mcthylacid ester chloridequinoline M.p. 73 47 4-Chlorophcnyl-thiol,2-Dihydro-4.6-dimethylcarbonic acid ester quinoline chloride 484-Chlorophcnyl-thiocarhonic L2-Dihydro-3-mcthylacid ester chloridequinolinc 49 4-C hlorophcn yl-thiol.2-Dihydro-8-methylcarbonic acidester quinoline chloride 50 B-Naphthyl-thiocarbonicl,2,3,4-Tetrahydro-4- acid ester chloride methyl-quinoline What isclaimed is:

l. A compound of the formula:

Ar-O-C- 3. A compound according to claim 2 wherein Ar is napthylt 4. Acompound according to claim 3 wherein Ar is naphthyl-( 2).

5. The compound according to claim 1 which is 2.3-

dihydro-N-[ naphthyl-( 2 )-oxy-thiocarbonyl]-l ,4- benzothiazine.

6. The compound according to claim I which is 2,3-

dihydro-6-methyl-N-I napthyl-( 2 )-oxy-thiocarbonyl]- 1,4-benzothiazine.

7. The compound according to claim 1 which is 2,3-

dihydro-6-trifluoromethyl-N-[naphthyl-( 2 )-0xythiocarbonyl l,4-benzothiazine.

8. The compound according to claim 1 which is 2,3-

dihydro-Z-methyl-N-lnaphthyl-( 2 )-oxy-thiocarbonyl]- 1,4-benzothiazine.

9. The compound according to claim 1 which is 2,3-

dihydro-2.6-dimethyl-N-[naphthyl-( 2 )-oxythiocarbonyl1- l,4-benzothiazinc.

10. The compound according to claim 1 which is 2,3-

dihydro-S ,6-benzo-N-l naphthyl-( 2 )-oxythiocarbonyl1- l,4-benzothiazine.

11. The compound according to claim 1 which is 2.3-

dihydro-N-[ 4-fluorophenoxy-thiocarbonyl]- l ,4- benzothiazine.

12. The compound according to claim 1 which is 2,3-

dihydro-N-[4-chlorophenoxy-thiocarbonyll-l ,4- benzothiazine.

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein Y is -CH2CH2-.
 3. A compound according to claim 2 wherein Ar is napthyl.
 4. A compound according to claim 3 wherein Ar is naphthyl-(2).
 5. The compound according to claim 1 which is 2,3-dihydro-N-(naphthyl-(2)-oxy-thiocarbonyl)-1,4-benzothiazine.
 6. The compound according to claim 1 which is 2,3-dihydro-6-methyl-N-(napthyl-(2)-oxy-thiocarbonyl)-1,4-benzothiazine.
 7. The compound according to claim 1 which is 2,3-dihydro-6-trifluoromethyl-N-(naphthyl-(2)-oxy-thiocarbonyl)-1,4 -benzothiazine.
 8. The compound according to claim 1 which is 2,3-dihydro-2-methyl-N-(naphthyl-(2)-oxy-thiocarbonyl)-1,4-benzothiazine.
 9. The compound according to claim 1 which is 2,3-dihydro-2,6-dimethyl-N-(naphthyl-(2)-oxy-thiocarbonyl)-1,4 -benzothiazine.
 10. The compound according to claim 1 which is 2,3-dihydro-5,6-benzo-N-(naphthyl-(2)-oxy-thiocarbonyl)-1,4-benzothiazine.
 11. The compound according to claim 1 which is 2,3-dihydro-N-(4-fluorophenoxy-thiocarbonyl)-1,4-benzothiazine.
 12. The compound according to claim 1 which is 2,3-dihydro-N-(4-chlorophenoxy-thiocarbonyl)-1,4-benzothiazine. 